Methylation completely stopped working...Can’t find the missing cofactor.

[DB_2014]

I’ve spent the last year trying to keep methylation working consistently, and I keep hitting some invisible roadblock. I eat large amounts of oysters (very high in zinc/copper) and lots of liver (high in copper/iron) to cover some of my micronutrient cofactor based.

My first round with methylation was in June 2018. My first dose of Methylfolate + MethylB12 hit me like a train. My brain fog cleared, insomnia gone, joint pain vanished, skin cleared up overnight....The improvements were insane. Over the course of June 2018-August 2018, I continued dosing the Methylfolate and methyl b12 along with potassium, carnitine, and a Adeno B12. By September 2018, I felt nothing from even a 30 mg dose of Methylfolate or a 30 mg dose of Methyl B12. I abandoned methylation from until February 2019 when I attempted another dose of methylfolate/methyl b12. Again, I had miraculous improvement in all symptoms. This lasted maybe a month, and then stopped again.

I’ve tried every cofactor I can think of without any reaction:

-Lithium
-Molybdenum
-Potassium
-Magnesium
-B1, B2, B3, B5, B6, Biotin
-Managnese
-Even tried supplement iron/zinc/copper although I’m getting plenty from oysters and liver.
-SAM-E
-TMG (had a massive initial reaction to this, then nothing)
-Betaine HCL (had an initial reaction to this as well, then nothing).

Has anyone else experienced these invisible road blocks? Is there anything missing from my list? Anything else I could try?

My main symptoms that methylation used to improve are systemic joint pain, insomnia, brain fog, and skin.

 

[Hip]

It's not unusual in ME/CFS for treatments which worked for a while to stop working. It does not necessarily mean you are missing some cofactor.

 

[percyval577]

Why do influences do stop working? If it´s a medical I guess it might partly be because the body has learned to clean from it effectively or to readjust other factors of a (rather ill) homeostasis.. If it´s a supplement there might be a chances that you have missed something.

B12 helps me for sure for one reason: it´s a scanvanger of NO or a blocker of NOS. Then there is the methylatation-folate cycle action.
B12 has an effect on the machinery of epigentics. Along with the methylation there are some other -ations in epigentics, e.g. acetylation. It´s speculative, but you can try a drop or half a drop of acetate, hoping that it would help any acetylation.
In my case it seems to have an effect, need to look at it further: I take juice from a lemon in 1l water, add two drops of B12 and now also [half a drop of vinegar for] acetate. Drinking from it (usig a straw) over some time is very nice. The citrate acid in lemons I suppose to chelate metals, which I want to reconfigurate in the brain, so at another time I eat chocolate which contains a lot of metals.
It´s on top of some vitB´s (2,1,7, will look at 5), extra selenium, and a restricting manganese diet in my case (iNOS is manganese dependent).

 

[Hip]

Only hydroxocobalamin is an NO scavenger.

 

[percyval577]

Thank you. I f am remembering rightly, cyanocobalamin is the molecule for storage and can get converted into methycobalamin which is the (most?) active molecule, and, well I have forgotten what´s about hydroxycobalamin (which is used in injections), but if I am remembering rightly, all three forms can get converted into each other.

I havn´t read this article already:
Inhibition of nitric oxide synthase by cobalamins and cobinamides Weinberg et al 2009

 

[sunshine44]

Have you ever looked at the Root Cause protocol? Its a very interesting theory on the specific steps in the body that happen so that methylation, etc. can return to baseline.

 

[JES]

I would concur that there likely isn't anything missing per se, more likely your body has adapted and regulated back to the "sickness state", which the supplements temporarily took you out of. The more I read about it, the more common this pheonomenon seems to be and it also applies to other diseases like for example depression, where antidepressant "poop-out" is a common pheonomenon. A Finnish ME/CFS patient/activist has documented her response to hundreds of supplements and drugs on this excellent site and the result has mostly been similar for me, i.e., supplement X stops working after time X.

 

[BeADocToGoTo1]

If this has already been covered in another thread, please ignore. But just in case you have not looked into this, have you tested for nutrient deficiencies or any form of malabsorption or microbiome dysbiosis which can cause nutrient deficiencies?

Some tests to consider:

1. Genova Diagnostics - FMV - Gives a great overall picture of nutrient deficiencies, neurotransmitter metabolites, microbiome dysbiosis, pancreatic enzyme issues, and many more. Biochemistry and metabolomics in practice. This test should be standard for all primary care and family practice doctors as a regular preventative maintenance test, and for anything chronic or hard to diagnose. Great Plains Laboratories has similar tests.

2. Genova Diagnostics - Comprehensive Digestive Stool Analysis 2.0 with Parasitology (microbiome dysbiosis indicators), Fecal Fat Distribution (checks if you have issues with different types of fat intake and digestion), Elastase (for EPI, pancreas enzyme marker)and Chymotrypsin (for EPI, pancreas enzyme marker). Doctor's Data has similar tests.

3. Small intestinal bacterial overgrowth (SIBO) breath test, for example, Commonwealth Diagnostics International. But the first one will also provide you with SIBO indicators.

But also look at HbA1c as a quick, standard indicator of excess sugar intake which impacts your microbiome, pancreas functioning amongst many other things. 5.2% or lower is what I strive for.

There are many reasons for malabsorption and nutrient deficiencies often overlooked by doctors, so it would be good to rule out things like exocrine pancreatic insufficiency (EPI), small intestinal bacterial overgrowth (SIBO), Candida yeast overgrowth, food sensitivities or allergies, gluten sensititivity, Chrohn's etc.

One other (often touchy) subject is food and beverage. Have you taken an honest hard look at all your food and beverage intake?

And sometimes too much supplementation can backfire (personal experience). Once certain deficiencies or causes of deficiencies have been remedied, continuing supplementation can cause issues by causing imbalances (e.g. copper/zinc, vitamin D/calcium). Have you tried stopping temporarily or reducing supplementation, giving the body a rest to try to absorb the nutrients from healthy food, and then slowly cycling back in one at a time? Have you retested for nutrient deficiencies after a while of supplementation?

 

[BodyMindSpirit77]

Hi, I suppose you could:
- lower your b12 intake, let's say, maybe a very few mg every 2 weeks (methylcobalamin and adenosylcobalamin), or even less frequently (1 monthly or less),
- take 2-3 times per day max 25 mg of riboflavin ,
- take methylfolate as needed (maybe 100-250 mcg once or twice daily, or less or more, depending on what works better for you),
- p5p 2-3 times a week, no more, with some thiamine and B3 (no more than 30 mg of b3),
- some magnesium and potassium chloride.

That's why great amount of b12 impair riboflavin use, and can also give B2 deficiency. That's because riboflavin (vitamin B2) is the precursor for FAD, the cofactor for methylenetetrahydrofolate reductase, whose actyivity is pushed by excessive doses of b12 and folate adviced in this forum, so that the result is a emptying of minimum stocks of b2.

Now, it takes 1-3 months to replenish b2 and restore FAD dependent enzymatic activity. And it's important to take methylfolate also, because b2 and high doses of b12 already stored will deplete your folate very quickly.

This is why high doses of methylcobalamin used in this forum are totally wrong, not to mention that it accumulates and there is no need to take it daily, unless you have severe deficiency, and only in the first few weeks.

This is the main error of the protocols used here.. high daily doses of b12 and impairment of FAD activity.. that's why people feel great at first and after a few weeks or months feel bad again.

So, to answer to your question, the missing cofactor could be Riboflavin (maybe..).

Unfortunately I can't say anything about the doses.. and no more about frequency of taking supplements.. it depends on individuals.
But hope this helps.

Davide.

 

[Saint George]

@DrHouse_Italy

This is fascinating and may explain tons of my issues with b vitamins. It is so hard to uncover which one is creating the unbalance and causing my severe brain fog each afternoon after morning Bs. Do you have any more information or sources about B12 pushing you into B2 deficiency? If I am taking 5mg of B12 daily (methyl/hydrox/and adeno) and 1mg folate, Seeking Health B Minus (complex with no folate and b12) and high doses of extra B1, could this be folate and b2 deficiency? My Genova labs showed folate, biotin, and b1 deficiency (red), and borderline (yellow) deficiency of b12, b6, and b2. I have no CBS mutations and sulfite supplements (sulphuraphane, NAC, taurine, and any others) also give me this fog.

 

[Hip]

That's why great amount of b12 impair riboflavin use, and can also give B2 deficiency.

b2 and high doses of b12 already stored will deplete your folate very quickly.

it takes 1-3 months to replenish b2 and restore FAD dependent enzymatic activity.

Would you be able to provided references for the above three statements please?

 

[BodyMindSpirit77]

Hi,
there is no scientific article regarding B2 deficiency induced by excess b12, because there is no data about such high chronic doses in scientific literature. There are some articles about chronic exposure to methylcobalamin, but not such high doses. So, the discourse is, yes, speculative, but is based on what we know about the biochemical pathways in methylation and folate/b12/riboflavin metabolism.

I've seen in this forum that some people strongly advice taking very high doses of methylcobalamin and folate, even without no reference for this. Just because that's working for them. I've also read a topic about insatiable needing of folate and potassium if they add some riboflavin to this protocol.. but that is so obvious!! What I'm searching to say is.. how is it possibile to even think to supplement with high doses of methylcobalamin and methylfolate without considering the role of riboflavin which is part of the protein MTHFR? If you look into these pathways you can see that even 5-methylfolate if in excess will go back through MTHFR to 5,10-methylenetetrahydrofolate, for pyrimidine biosynthesis, and this will consume again riboflavin (FAD).

I'm not here to tell you what is wrong or right, or to do so or that, just consider that this protocol will give surely a suboptimal riboflavin status, and this in years will impair your energy production and antioxidant system, and will predispose you to neurodegenerative disease, or, if all is gonna go well, to chronic pain and exercise intolerance. I just want you to reconsider such high doses and the importance on NAD / FAD cofactors in this process.

Saint George, I think it's better reduce those 5 mg of methylcobalamin. Think about the fact that b12 storage needs, in a healthy person, more than 4 years to deplete.. I think that taking it once monthly is more than enough, after you have filled up the stocks. Maybe, some (max 250 mcg per time) folinic acid, apart from the methylfolate (metafolin or quatrefolic, max 250 mcg at a time) to avoid methyltrap, would be a good idea to economize the riboflavin. So, I suggest monthly active b12 and low doses of folate (methyl-folate and folinic, detached from each other) how many times a day is needed, riboflavin daily, and the other cofactors. B1 is a great micronutrient (think that benfotiamine can partially reverse the amyloid accumulation in brain in Alzheimer Disease, in recent studies) , but I would not take it daily until the full FAD activity is restored.
I apologize if I can't, and won't, give any dosage.. because there is no standardized protocol that fits to everyone.
Please, stay healthy and don't affect your energy production.
Love and Joy.

Davide.

 

[Hip]

there is no scientific article regarding B2 deficiency induced by excess b12, because there is no data about such high chronic doses in scientific literature. There are some articles about chronic exposure to methylcobalamin, but not such high doses. So, the discourse is, yes, speculative, but is based on what we know about the biochemical pathways in methylation and folate/b12/riboflavin metabolism.

If you are speculating or hypothesizing about something, it's usually a good idea to say this. For example, you can say: "My speculation is that very high doses of B12 might cause a B2 deficiency".


Generally speaking, the methylation protocol has not turned out to be a great treatment for ME/CFS.

This forum poll showed that methylation compares badly to other ME/CFS treatments: only 3% of patients made a major improvement using the methylation protocol, whereas for example 50% made a major improvement using Valcyte, and 13% made a major improvement on oxymatrine or LDN.

I've seen in this forum that some people strongly advice taking very high doses of methylcobalamin and folate, even without no reference for this. Just because that's working for them.

The use of high-dose B12 as a treatment for ME/CFS goes back a long time. Nobody knows why it works. It does not mean that ME/CFS patients are deficient in B12, because supraphysiological doses of vitamins have effects which go beyond just meeting daily nutritional requirements.

Dr Myhill has a webpage on B12 for ME/CFS.

 

[BodyMindSpirit77]

you're right, but the fact that pushing methylation will deplete B2 is so clear if one chews a bit of biochemistry, that I really had the urge to subscribe just to tell "hey people, look at the fact that you're are going toward illness if you continue to do so" (always speculating ).

The use of high-dose B12 is just a cure for B12-deficiency. Even the recent guidelines on Multiple Sclerosis strongly advice NOT to take high-dose B12 for fatigue MS-related. I think, indeed, that the keys we should look at are folates, NAD and FAD, and B12 is just a piece of this puzzle, in the extent it's needed for optimal folate metabolism.. they go hand in hand, but all have to be balanced. Such chronic high doses of B12 (it looks like there's a balloon to fill with b12 and the more the better..) are, in my humble opinion, totally insane and potentially dangerous.

 

[Hip]

you're right, but the fact that pushing methylation will deplete B2 is so clear if one chews a bit of biochemistry

You might like to put your theory to Dr Greg Russell-Jones, who can be contacted via his website which sells transdermal B12 oils. His transdermal oils provide a dose of methylcobalamin and adenosylcobalamin equivalent to a 2,000 mcg injection. Greg has a PhD in biochemistry, and his area of expertise is B12 metabolism.

In my email conversations with him, Greg detailed his view that B2 supplementation is important in order to get the benefits from a high-dose B12 protocol. But he did not mention anything about high-dose B12 leading to B2 deficiency. More info on Greg's views in this thread.

 

[BodyMindSpirit77]

thanks, I'll do !

My "theory" is based on what we know about metabolic pathways, on the study of literature, and on the empirical data on my patients.

I also applied this "methylation protocol" at the beginning, but at best it worked just for a few weeks. So I realized that some corrections aimed at restoring FAD activity and Optimizing NAD and folate, in 2-3 months determined a marked improvement. But, it's my opinion of course, ...

Kind regard, Sarah !
Davide.

 

[Saint George]

@DrHouse_Italy

I really think you are onto something with me. So, for that, I thank you. Question about B2...after taking approximately 100mg of FMN/R5P spaced throughout the day (25mg each), I have been feeling so much better with regards to anxiety, energy, brain fog, depression, etc. I didn't reread this thread update and have still been taking b12 and folinic acid, and did have some fog/nervousness in the afternoon. I am going to back off the b12 for a while. You mentioned cycling the two types of folate, but I can't tolerate methylfolate and am homozygous 677t, is that ok to just be on folinic? My body will make some methylfolate from it right? Methylfolate gives me anxiety and makes me extremely clammy and feel like I'm going through some kind of withdrawal. It's very weird. My genova labs showed very elevated FIGLU too, which means folinic acid is needed, not methylfolate. My question on B2 is if I only take R5P, will that not restore FAD activity? That is a different derivative of B2 (FMN). Should I be taking regular old riboflavin and let my body do the work? I haven't taken regular riboflavin in years since I used to slam 5 hour energy shots - haha. Since discovering methylation I have always been taking riboflavin-5-P.

@Hip

Based on your other post, yesterday I ordered the b complex oil from Dr. Greg and hoping it will work as it doesn't contain folate, but does contain some adenosylcobalamin. Dr. Greg mentions the cofactors of selenium, iodine, and molybdenum if you are going to be on a b12 protocol, so I have begun taking that as well. Do you know how I can figure out how much b12 is in his b complex oil?

 

[BodyMindSpirit77]

@DrHouse_Italy

I really think you are onto something with me. So, for that, I thank you. Question about B2...after taking approximately 100mg of FMN/R5P spaced throughout the day (25mg each), I have been feeling so much better with regards to anxiety, energy, brain fog, depression, etc. I didn't reread this thread update and have still been taking b12 and folinic acid, and did have some fog/nervousness in the afternoon. I am going to back off the b12 for a while. You mentioned cycling the two types of folate, but I can't tolerate methylfolate and am homozygous 677t, is that ok to just be on folinic? My body will make some methylfolate from it right? Methylfolate gives me anxiety and makes me extremely clammy and feel like I'm going through some kind of withdrawal. It's very weird. My genova labs showed very elevated FIGLU too, which means folinic acid is needed, not methylfolate. My question on B2 is if I only take R5P, will that not restore FAD activity? That is a different derivative of B2 (FMN). Should I be taking regular old riboflavin and let my body do the work? I haven't taken regular riboflavin in years since I used to slam 5 hour energy shots - haha. Since discovering methylation I have always been taking riboflavin-5-P.

@Hip

Based on your other post, yesterday I ordered the b complex oil from Dr. Greg and hoping it will work as it doesn't contain folate, but does contain some adenosylcobalamin. Dr. Greg mentions the cofactors of selenium, iodine, and molybdenum if you are going to be on a b12 protocol, so I have begun taking that as well. Do you know how I can figure out how much b12 is in his b complex oil?

Hi, you' re welcome !
I think that the cheap simple Riboflavin is sufficient.. no need for the expensive R5P. I would take max 25 mg, max three times per day. Consider that the more you take riboflavin, the more you'll be able to metabolize methylfolate.. and any headaches and muscle contractures will testify to the need for methylfolate. You're right about the fact that folinic acid should be converted into methylfolate, but if the pathway has been down-regulated this should realize a relative methylfolate deficiency (low levels of neurotransmitters, serotonin primarily). Remember that most of the times a person is unable to tolerate methylfolate, this is a sign of low FAD activity.. so after a few days of taking B2 without B12 you not only will be able to take methylfolate, but you'll need it in order to "adjust" what has been locked. Don't think you'll always need the same dosage of b2 and folate, adjust it day by day. Regarding minerals, molybdenum is really important if you need to reactivate FAD activity. Unfortunately I have no experience with B-complex oil from Dr. Greg.. can't help you about this, but it would be better back off the B12 while increasing the B2, otherwhise you could have hypermethylation symptoms, and much more confusion regarding the right way to follow. Try not to overdose the folate.. if you'll develop drowsiness, apathy, this would be the case. And keep your potassium balanced (chloride, not other forms).
Hope this will help you, and some others.

 

[BodyMindSpirit77]

sorry.. I forgot.. keep you magnesium balanced too, specially if you take P5P (no need to overdose P5P as it has a half-life of 15-20 days)..

 

[Hip]

Do you know how I can figure out how much b12 is in his b complex oil?

I imagine each product will contain a similar dose.

When you get the bottle, it comes with an instruction and info sheet. On mine it says each dose (each pump of the bottle) provides 2.5 mg (2,500 mcg) of B12. Since Greg estimates that 80% of his B12 oils are absorbed transdermally, you are going to get around 2 mg absorbed into the bloodstream per dose.

That's equivalent to being given four B12 injections in one go (as B12 injections typically have a 0.5 mg dose).

I did pretty well with his B12 oils: they noticeably reduced brain fog. But after around 4 months they stopped working for me, even though I was taking all the cofactors, including B2.